A new study by researchers from the Medical University of South Carolina-USA and The City College of New York has found that home-based transcutaneous auricular vagus nerve stimulation (taVNS) therapy can help in Long COVID.
The trial was registered onClinicalTrials.gov under the identifier: NCT04638673. https://clinicaltrials.gov/ct2/show/NCT04638673
The study findings were published on a preprint server and are currently being peer reviewed.
Non-invasive brain stimulation (NIBS) has been suggested as a possible approach to manage COVID-19(13–15). Various NIBS techniques have demonstrated an anti-inflammatory effect, with a reduction of pain symptoms and improvement in cognition, pointing towards their potential ability to assist in the management of neuropsychiatric disorders.
Of particular interest is the NIBS modality known as transcutaneous auricular vagus nerve stimulation (taVNS). taVNS involves stimulation of the auricular branch of the vagus nerve (ABVN) that bilaterally innervates the human ear (15–23). Stimulation of the ABVN has demonstrated promising anti-inflammatory(24, 25), anti-pain(26), and antidepressant effects(27).
These effects are driven via the vagus nerve, activating both central and peripheral mechanisms that change behavior. Relative to other neuromodulation interventions, taVNS offers in principle advantages for home-use including self-administration, battery powered device, low cost, and a robust tolerability safety profile. However, most taVNS trials have been clinic based.
Transition of clinical NIBS technology from laboratory to home use requires consideration of device and protocol suitability, and taVNS protocols offer potential advantages to many NIBS technologies because they are especially linked to biomarker (e.g., heart rate, blood pressure) monitoring (28, 29) which facilitate safety monitoring.
The onset of the COVID-19 pandemic provided an opportunity to accelerate investigating the use of completely remote, self-administered, telemedicine approaches to brain stimulation studies. Building on that concept, we created an at-home, remote-monitored, self-administrable taVNS system, integrated with telehealth and biomarker monitoring, to manage symptoms associated with Long COVID in individuals who had prior infection with SARS CoV-2 virus.
In this trial, we designed and developed a completely remote, double-blind, telemedicine controlled, transcutaneous auricular vagus nerve stimulation system (taVNS) with companion real-time heart rate monitoring. We then investigated the use of this novel, self-administrable taVNS system during the early COVID-19 pandemic (2020–2021) to understand its safety, feasibility, and potential to manage Long COVID symptoms in the home setting. Each participant self-administered taVNS twice daily, in one-hour sessions, six days a week for up to 4 weeks.
This completely remote and virtual (no in-person visits) brain stimulation approach was feasible, with participants learning how to reliably self-administer stimulation within their first five sessions. Furthermore, stimulation was safe, even at home, with no bradycardia or serious adverse events occurring during the stimulation sessions. Lastly, there was a mild improvement in overall self-reported Long COVID symptoms, as well as mental fatigue, although this small study was not powered to detect clinical effects.
It has been over two years since the beginning of the COVID-19 pandemic, but the persistent, long-term impacts of the SARS-CoV-2 virus are still not understood. Long COVID is a complex and heterogenous disorder that involves several central and peripheral symptoms that are difficult to individually address from a mechanistic perspective.
Even with these challenges, a main underlying hypothesis is that these prolonged symptoms are due to extended neuroinflammatory response. Interestingly, although vagus nerve stimulation (VNS) has been used in humans since 1997 for treating refractory epilepsy(33), there recently has been increased enthusiasm surrounding the use of VNS for several inflammatory disorders in humans such as rheumatoid arthritis(34–36).
These anti-inflammatory effects have been validated in animal models demonstrating the cellular, molecular, and central anatomical mechanisms that mediate central modulation of immune functions suggesting attenuation of cytokine storm(37) and activation of vagal mediated inflammatory response.
Early evidence from an alternative noninvasive VNS trial (gamma Core device targeting the cervical bundle of the vagus nerve by applying electrical stimulation to the neck landmarked by the carotid sheath) suggests that stimulation of the vagus nerve has mild anti-inflammatory effects in 97 COVID-19 patients(38). Although non-invasive vagus nerve stimulation may be administered with a variety of different technologies, evidence suggests it potentially engages an anti-inflammatory mechanism that should be further explored in future trials.
About transcutaneous auricular Vagus Nerve Stimulation
Recently, a noninvasive form of VNS known as transcutaneous auricular vagus nerve stimulation (taVNS) has emerged (George 2000). Unlike surgically-implanted VNS, taVNS is an inexpensive, low-risk, easy to administer, and portable option to modulate the vagus system. taVNS is appealing as it allows for rapid translation of basic VNS research in exploring potential treatments of central and peripheral disease.
Vagus nerve stimulation (VNS) involves surgical implantation of electrodes onto the cervical branch of the vagus nerve. Electrical pulses are delivered to the vagus nerve via an implanted pulse generator (IPG) surgically implanted in the chest. VNS is currently FDA-approved for epilepsy, refractory depression, and chronic obesity and long-term safety of VNS is well established.
taVNS on the other hand, delivers electrical stimulation to the auricular branch of the vagus nerve (ABVN), an easily accessible target that innervates the human ear (Peukar and Filler 2002). Over the last decade, several groups have demonstrated the safety and tolerability of this method, including central and peripheral nervous system effects, and behavioral effects in neuropsychiatric populations (Kreuzer et al 2012, Clancy et al 2014, Rong et al 2016, Bauer et al 2016 ). taVNS is also being explored in individuals to enhance cognitive and social functioning (Jacobs et al 2015,Jongkees et al 2018,Colzato et al 2018). Furthermore, side-effects of taVNS are minimal, with skin irritation or redness being the most common side-effect.
The optimal stimulation targets are still being explored (Badran et al 2018), however, the two most common placements are the anterior wall of the outer ear canal (tragus) and the cymba conchae. Sham stimulation may be conducted by stimulating the earlobe of the ear, an area believed to have minimal ABVN innervation. Alternatively, sham may be delivered via a passive control method in which electrodes are attached to active sites, but no stimulation is delivered. Stimulation parameters used have varied between groups, however according to the literature, stimulation is delivered in a pulsatile fashion (pulse width: 250–500 μs, frequency: 10–25 Hz) and delivered at an individualized constant current (< 5 mA).
taVNS Stimulator by Soterix Medical
Based on the revolutionary mini-CT platform, Soterix Medical introduces the first transcutaneous auricular vagus nerve stimulator (taVNS) specially developed for clinical (human) brain stimulation research. The system provides the necessary pulse parameter settings (frequency, train duration, inter-train interval, session duration) that allow testing commonly used protocols. With option to unlock device in as many as three different ways (code-based , time-based, ElectraRx web-based), the system provides researchers with flexibility to plan taVNS trials as they wish.
The Soterix Medical taVNS ear stimulation electrodes are the first and only electrodes optimized specifically for rigorous human trials.
The Soterix Medical EASY-Clip electrode is designed for ease-of-use and flexible application. The optimal spring mechanism has been validated to ensure a comfortable and robust contact whether targeting the auditory canal (tragus) or the ear lobe for SHAM stimulation.
The Soterix Medical RELIfit-Tragus solution is uniquely designed to hook around the ear for fail safe positioning in real-world applications, The simple and convenient design offers the option for either short duration (saline sprayed sponge) or extended duration (gel) applications.
The Soterix Medical RELI-Stick electrode offers unmatched versatility. These single use flexible hydrogel electrodes with optimal adhesion performance can be positioned anywhere on the ear for ultimate customization and subject comfort.
- George, M.S. et al. Vagus nerve stimulation: a new form of therapeutic Brain Stimulation.CNS Spectrums. 5 (11), 43-52 (2000).
- Peuker, E.T., & Filler, T.J. The nerve supply of the human auricle. Clinical Anatomy. 15 (1), 35-37 (2002).
- Kreuzer, P.M. et al. Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Frontiers in Psychiatry. 3, 70 (2012)
- Clancy, J.A. et al. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimulation. 7 (6), 871-877 (2014).
- Bauer, S. et al. Transcutaneous vagus nerve stimulation (tVNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial (cMPsE02). Brain Stimulation. 9 (3), 356-363 (2016).
- Jacobs, H.I., Riphagen, J.M., Razat, C.M., Wiese, S., & Sack, A.T. Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. Neurobiology of Aging. 36 (5), 1860-1867 (2015)
- Jongkees, B.J., Immink, M.A., Finisguerra, A., & Colzato, L.S. Transcutaneous Vagus Nerve Stimulation (tVNS) Enhances Response Selection During Sequential Action. Frontiers in Psychology. 9, 1159 (2018).
- Colzato, L.S., Ritter, S.M., & Steenbergen, L. Transcutaneous vagus nerve stimulation (tVNS) enhances divergent thinking. Neuropsychologia. 111, 72-76 (2018).
- Badran, B.W. et al. Tragus or cymba conchae? Investigating the anatomical foundation of transcutaneous auricular vagus nerve stimulation (taVNS). Brain Stimulation. 11 (4), 947-948 (2018).